Pathophysiology of the dopaminergic neurons of the substantia nigra pars compacta (SNC) underlies many of the symptoms of neurological disorders such as Parkinson's disease and psychoses such as schizophrenia. These neurons and their synaptic targets also serve as the sites of action of stimulant drugs of abuse such as cocaine and antipsychotic drugs. Dopamine neurons fire in three patterns, namely random, pacemaker, and bursty firing pattern. The different firing patterns, especially the bursty pattern, of the nigrostriatal neurons of the SNC have been correlated with environmental stimuli relevant to reward contingencies. Also spikes of dopaminergic neurons of the SNC clustered in bursts may release more dopamine at synaptic targets than single spikes. The fact that these cells fire differently in vitro than in vivo suggests that the afferent control of these neurons is critically involved in the regulation of their firing pattern. The main hypothesis to be tested in this proposal is that the firing pattern and modulation of dopaminergic neurons is controlled through disinhibition in large part by the GABAergic afferents to these cells using electrophysiological techniques combined with controlled local application of selective antagonists for different receptors. By investigating how receptors on and afferents to dopaminergic neurons affect firing pattern and understanding which receptors mediate the afferent control of these cells, a better understanding can be achieved of how and to what extent dopaminergic neurons are controlled by afferents.